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Modulators of p-selectin glycoprotein ligand 1

a technology of pselectin and glycoprotein, which is applied in the direction of immunological disorders, drug compositions, peptides, etc., can solve the problems of limiting the therapeutic application of these two antibodies, hampered attempts to use fas and tnfr2 molecules to control unwanted t cells, etc., to prevent immune activation, induce t cell depletion, and/or apoptosis in

Inactive Publication Date: 2010-04-01
ABGENOMICS COOPERATIEF U A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0042]An advantage of the invention is that it can induce the depletion of T cells and / or the induction of apoptosis in T cells without causing an associated unwanted or harmful immune response. For example, in some embodiments the administration to an individual of an anti-PSGL-1 antibody or a multimeric compound described herein does not result in an unwanted elevation in the levels of inflammatory cytokines such as IL-2 or TNF-alpha.
[0043]Another advantage of the invention is that it causes the depletion of T cells by the use of agonistic compositions that induce apoptosis of T cells. Accordingly, the invention provides for active immunosuppressive methods rather than passive immunosuppression that results from using antagonistic compositions (e.g., antagonistic anti-PSGL-1 antibodies or antagonistic soluble selectin fragments) that act by binding immune receptors and preventing immune activation mediated by such receptors.
[0044]Another advantage of the invention is that it allows for the targeting of a cell surface protein, PSGL-1, whose expression is largely limited to leukocytes, and in particular T cells and NK cells. Therefore, the compounds described herein generally do not induce significant levels of apoptosis of other cell types such as liver cells. The targeting of T cells and NK cells (an important CD3− cell type involved in transplantation rejection) for selective depletion, without significantly inducing life-threatening systemic cytokine responses and damaging other organ systems, is a desired characteristic of an immunosuppressive agent.
[0045]Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of a conflict in terminology, the present specification will control. In addition, the described materials and methods are illustrative only and are not intended to be limiting.
[0046]Other features and advantages of the invention will be apparent from the following detailed description and the claims.

Problems solved by technology

Attempts to use Fas and TNFR2 molecules to control unwanted T cells have been hampered by the fact that these two molecules are expressed not only on immune cells, but also on several other important organ systems like liver.
This expression pattern potentially limits the therapeutic application of these two antibodies (Ogasawara et al.

Method used

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  • Modulators of p-selectin glycoprotein ligand 1
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Examples

Experimental program
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example 1

Preparation of an Anti-T Cell Apoptosis Inducing Protein (“TAIP”) Monoclonal Antibody

[0107]A TAIP-specific monoclonal antibody was generated by applying the well known cell fusion methods of Kohler and Milstein ((1976) European Journal of Immunology 6:511-519) to produce a hybridoma secreting desired antibodies. Antibody-producing cells from a hamster injected with Concanavalin A (Con A)-activated Balb / c spleen T cells were fused with a myeloma cell line to form an antibody secreting hybridoma. The two populations of cells were fused with polyethylene glycol, and the resulting antibody producing cells were cloned and propagated by standard tissue culture methods. One hybridoma generated according to these methods secreted a monoclonal antibody, designated TAB4, that was able to induce T cell apoptosis in vitro and deplete T cells in vivo. The protein recognized by TAB4 was designated T cell apoptosis inducing protein (TAIP).

[0108]C57BL / 6J (B6) and BALB / c mice were purchased from the...

example 2

Preparation of a Mouse Spleen Cell Suspension and the Activation and Enrichment of T cells

[0110]Mouse spleen was immersed in 8 ml of Hank's balanced salt solution (HBSS), gently minced with a sterile cover slip, transferred to a 15 ml centrifuge tube (Costar), and spun at 200×g for 5 minutes. The supernatant was discarded and the cell pellet was resuspended in the residual buffer by gently tapping the wall. The contaminating red blood cells (RBC) were lysed by the addition of 1 ml of RBC lysis buffer (0.6 M NH4Cl, 0.17 M Tris-base, pH 7.65), followed by a 2 min incubation at room temperature and rapid quenching with 9 ml of HBSS. The cells were pelleted at 200×g for 5 minutes, washed twice and resuspended in RPMI medium. The concentration and viability of cells in the mixture were determined with a hemocytometer (Cambridge Scientific Inc.) and Trypan blue exclusion.

[0111]The spleen cells were adjusted to a final concentration of 3×106 / ml with RPMI medium and Concanavalin A was added...

example 3

Apoptosis of Activated T cells

[0112]Activated T cells (see Example 2) were resuspended to a final concentration of 5×105 cells / ml in RPMI medium containing 5 ng / ml of IL-2, and treated with control Ig, TAB4, or anti-CD3 according to the conditions shown in Table 1.

TABLE 1Experiment groupsTreatment*Negative control3 ug / ml hamster Ig5 ng / ml IL-23 ug / ml cross-linker antibody (anti-hamster Ig)TAB43 ug / ml TAB4 hamster mAb5 ng / ml IL-23 ug / ml cross-linker antibody (anti-hamster Ig)Positive control1 ug / ml anti-CD3 mAb5 ng / ml IL-21 ug / ml cross-linker antibody (anti-mouse Ig)*Final concentration of the designated reagents in the medium.

[0113]After an incubation period of 18-24 hours, the extent of apoptosis in each culture was determined using the 7-AAD apoptosis assay. The treated cells were transferred to FACS tubes (Falcon), washed twice with ice-cold FACS solution (1% fetal bovine serum, 0.05% sodium azide in PBS), pelleted at 200×g at 4° C. The cells were resuspended in ice-cold FACS sol...

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Abstract

Multimeric compounds that bind to P-Selectin Glycoprotein 1 (PSGL-1) on the surface of T cells or natural killer (NK) cells can be used to induce T cell or NK cell depletion and / or to induce T cell or NK cell apoptosis. The multimeric compounds and methods of the invention can be used to control unwanted T cell- or NK cell-mediated immune responses in conditions such as inflammatory diseases, autoimmune diseases, transplant rejection, and allergic diseases.

Description

RELATED APPLICATIONS[0001]This application is a divisional of U.S. application Ser. No. 10 / 662,906, filed Sep. 15, 2003, which is a continuation-in-part of U.S. application Ser. No. 10 / 051,497, filed Jan. 18, 2002, which claims priority of U.S. Application No. 60 / 310,196, filed Aug. 3, 2001. The prior applications are incorporated herein by reference in their entirety.FIELD OF THE INVENTION[0002]The invention relates to compositions and methods for controlling immune responses.BACKGROUND OF THE INVENTION[0003]The control of unwanted immune responses is a critical issue in the treatment of diseases such as inflammatory diseases, autoimmune diseases, transplant rejection, allergic diseases and T cell-derived cancers. The activity of overly aggressive T cells can be controlled by immunosuppression or by the induction of immunological tolerance. Tolerance is defined as a state where the immune system is made unresponsive to an antigen, whereas immunosuppression, which decreases the immu...

Claims

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Application Information

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IPC IPC(8): A61K39/00C12N5/0783A61P37/06G01N33/48A61K39/395A61K45/00A61P35/00A61P37/08A61P43/00C07K14/705C07K16/28C12Q1/02G01N33/15G01N33/50G01N33/53G01N33/577
CPCA61K2039/505C07K14/70564C07K16/28C07K16/2896C07K2317/73C07K2319/30G01N2500/10G01N2800/52C07K2316/95A61P35/00A61P37/06A61P37/08A61P43/00
Inventor LIN, RONG-HWACHANG, CHUNG NAN
Owner ABGENOMICS COOPERATIEF U A
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